AP 151

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AP 151

• The Physiology of Neurotransmitters
• An excellent resource for this unit can be found
  at the following link
• http//nba.uth.tmc.edu/neuroscience/index.htm

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Synapses

• A junction that mediates information transfer
  from one neuron
• To another neuron
• Called neuro-synapses or just synapse
• To an effector cell
• Neuromuscular synapse if muscle involved
• Neuroglandular synapse if gland involve
• Presynaptic neuron conducts impulses toward the
  synapse
• Postsynaptic neuron transmits impulses away
  from the synapse
• Two major types
• Electrical synapses
• Chemical synapses

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Synapses

• Axodendritic synapse
• Axosomatic synapse
• Axoaxonic synapse

Figure 11.17
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Electrical Synapses

• Pre- and postsynaptic neurons joined by gap
  junctions
• allow local current to flow between adjacent
  cells. Connexons protein tubes in cell membrane.
• Rare in CNS or PNS
• Found in cardiac muscle and many types of smooth
  muscle. Action potential of one cell causes
  action potential in next cell, almost as if the
  tissue were one cell.
• Important where contractile activity among a
  group of cells important.

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Chemical Synapses

• Most common type
• Cells not directly coupled as in electrical
  synapses
• Components
• Presynaptic terminal
• Synaptic cleft
• Postsynaptic membrane (PSM)
• Chemical neurotransmitters (NTs) released by
  presynaptic neuron
• NT binds to receptor on PSM

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Chemical Synapse

• Events at a chemical synapse
• 1. Arrival of action potential on presynaptic
  neuron opens volage-gated Ca channels.
• 2. Ca influx into presynaptic term.
• 3. Ca acts as intracellular messenger
• stimulating synaptic vesicles to fuse with
• membrane and release NT via exocytosis.
• 4. Ca removed from synaptic knob by
• mitochondria or calcium-pumps.
• 5. NT diffuses across synaptic cleft and
• binds to receptor on postsynaptic membran
• 6. Receptor changes shape of ion channel
• opening it and changing membrane potential
• 7. NT is quickly destroyed by enzymes or
• taken back up by astrocytes or presynaptic
• membrane.
• Note For each nerve impulse reaching the
  presynaptic terminal, about 300 vesicles are
  emptied into the cleft. Each vesicle contains
  about 3000 molecules.

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Removal of Neurotransmitter from Synaptic Cleft

• Method depends on neurotransmitter
• ACh acetylcholinesterase splits ACh into acetic
  acid and choline. Choline recycled within
  presynaptic neuron.
• Norepinephrine recycled within presynaptic
  neuron or diffuses away from synapse. Enzyme is
  monoamine oxidase (MAO). Absorbed into
  circulation, broken down in liver.

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Synaptic Delay

• 0.2-0.5 msec delay between arrival of AP at
  synaptic knob and effect on PSM
• Reflects time involved in Ca influx and NT
  release
• While not a long time, its cumulative synaptic
  delay along a chain of neurons may become
  important.
• Thus, reflexes important for survival have only a
  few synapses
• Synaptic Fatigue
• Under intensive stimulation, resynthesis and
  transport of recycled NT my be unable to keep
  pace with demand for NT
• Synapse remains inactive until NT has been
  replenished

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Receptor Molecules and Neurotransmitters

• Neurotransmitter only "fits" in one receptor.
• Not all cells have receptors.
• Neurotransmitters are commonly classified as
  excitatory or inhibitory.
• Classification is useful but not precise. For
  example
• ACh is stimulatory at neuromuscular junctions
  (skeletal)
• ACh is inhibitory at neuromuscular junction of
  the heart ?
• Therefore, effect of NT on PSM depends on the
  type of receptor, and not nature of the
  neurotransmitter
• Some neurotransmitters (norepinephrine) attach to
  the presynaptic terminal as well as postsynaptic
  and then inhibit the release of more
  neurotransmitter.

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Postsynaptic Potentials

• NT affects the postsynaptic membrane potential
• Effect depends on
• The amount of neurotransmitter released
• The amount of time the neurotransmitter is bound
  to receptors
• The two types of postsynaptic potentials are
• EPSP excitatory postsynaptic potentials
• IPSP inhibitory postsynaptic potentials

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Excitatory Postsynaptic Potentials

• EPSPs are graded potentials that can initiate an
  action potential in an axon
• Use only chemically gated channels
• Postsynaptic membranes do not generate action
  potentials
• But, EPSPs bring the RMP closer to threshold and
  therefore closer to an action potential

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Inhibitory Synapses and IPSPs

• Neurotransmitter binding to a receptor at
  inhibitory synapses
• Causes the membrane to become more permeable to
  potassium and chloride ions
• Leaves the charge on the inner surface more
  negative (flow of K out of the cytosol makes the
  interior more negative relative to the exterior
  of the membrane
• Reduces the postsynaptic neurons ability to
  produce an action potential

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Summation

• A single EPSP cannot induce an action potential
• EPSPs must summate temporally or spatially to
  induce an action potential
• Temporal summation one presynaptic neuron
  transmits impulses in rapid-fire order
• Spatial summation postsynaptic neuron is
  stimulated by a large number of presynaptic
  neurons at the same time
• IPSPs can also summate with EPSPs, canceling each
  other out

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Summation
Figure 11.21
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Neurotransmitters

• Chemicals used for neuronal communication with
  the body and the brain
• 50 different neurotransmitters have been
  identified
• Classified chemically and functionally
• Chemically
• ACh, Biogenic amines, Peptides
• Functionally
• Excitatory or inhibitory
• Direct/Ionotropic (open ion channels)
• Indirect/metabotropic (activate G-proteins) that
  create a metabolic change in cell

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Neurotransmitter Receptor Mechanisms

• Direct neurotransmitters that open ion channels
• Promote rapid responses
• Examples ACh and amino acids
• Indirect neurotransmitters that act through
  second messengers
• Promote long-lasting effects
• Examples biogenic amines, peptides, and
  dissolved gases

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Channel-Linked Receptors

• Composed of integral membrane protein
• Mediate direct neurotransmitter action
• Action is immediate, brief, simple, and highly
  localized
• Ligand binds the receptor, and ions enter the
  cells
• Excitatory receptors depolarize membranes
• Inhibitory receptors hyperpolarize membranes

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Channel-Linked Receptors
Figure 11.23a
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G Protein-Linked Receptors

• Responses are indirect, slow, complex, prolonged,
  and often diffuse
• These receptors are transmembrane protein
  complexes
• Examples muscarinic ACh receptors,
  neuropeptides, and those that bind biogenic amines

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G Protein-Linked Receptors Mechanism

• Neurotransmitter binds to G protein-linked
  receptor
• G protein is activated and GTP is hydrolyzed to
  GDP
• The activated G protein complex activates
  adenylate cyclase
• Adenylate cyclase catalyzes the formation of cAMP
  from ATP
• cAMP, a second messenger, brings about various
  cellular responses

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G Protein-Linked Receptors Mechanism
Figure 11.23b
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G Protein-Linked Receptors Effects

• G protein-linked receptors activate intracellular
  second messengers including Ca2, cGMP, and cAMP
• Second messengers
• Open or close ion channels
• Activate kinase enzymes (phosphorylation rxns)
• Phosphorylate channel proteins
• Activate genes and induce protein synthesis!!

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Chemical Neurotransmitters

• Acetylcholine (ACh)
• Biogenic amines
• Amino acids
• Peptides
• Novel messengers ATP and dissolved gases NO and
  CO

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Neurotransmitters Acetylcholine

• First neurotransmitter identified (by Otto Loewi)
  and best understood
• Synthesized and enclosed in synaptic vesicles
• Degraded by the enzyme acetylcholinesterase
  (AChE)
• Released by cholinergic neurons
• All skeletal muscle motor neurons
• Anterior horn motor neuron ( Lower motor
  neuron)
• Some neurons in the autonomic nervous system
• All ANS preganglionic neurons (parasym. and
  sympathetic)
• All parasympathetic postganglionic neurons
  stimulating smooth muscle, cardiac muscle, and
  glands
• Symp. postganglionic neurons stimulating sweat
  glands
• Ach binds to cholinergic receptors known as
  nicotinic or muscarinic receptors

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Comparison of Somatic and Autonomic Systems
Figure 14.2
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Cholinergic Receptors Bind ACh

• Nicotinic receptors
• - Are ion channels (rapid acting)
• - On sarcolemma of skeletal muscle fibers
• - On dendrites and cell bodies of ALL
  postganglionic
• neurons of the ANS
• - Excitatory (open Na channels ? fast EPSP)
• Muscarinic receptor
• - Are G-protein couple receptors (complex
  intracellular
• functions)
• - On all parasympathetic target organs (cardiac
  and
• smooth muscle)
• - Are excitatory in most cases inhibitory in
  others

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Acetylcholine

• Effects prolonged (leading to tetanic muscle
  spasms and neural frying) by nerve gas and
  organophosphate insecticides (Malathion).
• ACH receptors destroyed by patients own
  antibodies in myasthenia gravis
• Binding to receptors inhibited by curare (a
  muscle paralytic agent
• blowdarts in south American tribes and some snake
  venoms.

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Neurotransmitters Monoamines/Biogenic Amines

• Include
• Catecholamines dopamine, norepinephrine (NE),
  and epinephrine (EP)
• Indolamines serotonin and histamine
• Broadly distributed in the brain
• Cats. are important sympathetic NTs
• Play roles in emotional behaviors and our
  biological clock

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Synthesis of Catecholamines

• AA tyrosine is parent cpd
• Enzymes present in the cell determine length of
  biosynthetic pathway
• Norepinephrine and dopamine are synthe-sized in
  axonal terminals
• Epinephrine is released by the adrenal medulla as
  a hormone

Figure 11.22
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BIOGENIC AMINES Norepinephrine

• Norepinephrine (aka Noradrenaline)
• Main NT of the sympathetic branch of autonomic
  nervous system
• Binds to adrenergic receptors (? or ? -many
  subtypes, ?1, ?2, etc)
• Excitatory or inhibitory depending on receptor
  type bound
• Very important role in attention and arousal -
  an organisms vigilance
• Also released by adrenal medulla as a hormone
• Feeling good NT
• Clinical Importance
• Thought to be involved in etiology of some
  bipolar affective disorders
• Removal from synapse blocked by antidepressants
  and cocaine
• Levels lowers in depressed pts. and higher in
  manic phase of bipolar dis.
• Release enhanced by amphetamines

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BIOGENIC AMINES Dopamine

• Dopamine
• Binds to dopaminergic receptors of substantia
  nigra of midbrain and hypothalamus
• Involved in important physiology functions
  including
• Motor control
• Coordinating autonomic functions
• Regulating hormone release
• Motivational behavior and reward i.e., a
  feeling good NT
• Hypothesized to be at the heart of the
  mechanisms of ALL addictive-
• drugs and behaviors. For example,
• Release enhanced by amphetamines
• Reuptake blocked by cocaine
• Deficient in Parkinsons disease
• Receptor abnormalities have been linked to
  development of schizo-
• phrenia

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Biogenic Amines Serotonin (5-HT)

• Synthesized from the amino acid tryptophan
• Since tryptophan not synthesized in humans, its
  levels available for synthesis of serotonin are
  dependent on diet.
• Diets high in tryptophan can markedly elevate
  serotonin levels
• May play a role in sleep, appetite, and
  regulation of moods (aggression)
• Low 5-HT levels associated with increased
  aggressiveness and risk taking
• Acts in a pathway that monitors carbohydrate
  intake, acting as a negative regulator of
  motivation to ingest carbohydrate
• Has led to the use of SSRIs (see below) as
  obesity pills (fenfluramine)
• Drugs that block its uptake relieve anxiety and
  depression and aggression
• SSRIs selective serotonin reuptake inhibitors
• Include drugs such as Prozac, Celexa, Lexapro,
  Zoloft
• Ecstasy targets serotonin receptors

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Neurotransmitters Amino Acids

• Include
• GABA Gamma (?)-aminobutyric acid
• Glycine
• Aspartate
• Glutamate
• Found only in the CNS

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Amino Acid Neurotransmitters

• Excitatory Amino Acids
• 1. Glutamate
• Indirect action via G proteins and 2nd messengers
• Direct action -- opens Ca channels (ionotropic)
• NMDA receptors (have a high permeability to Ca)
• Widespread in brain where it represents the major
  excitatory neurotransmitter
• Important in learning and memory!
• Highly toxic to neurons when present for extended
  periods
• - Stroke NT -excessive release produces
  excitotoxicity
• neurons literally stimulated to death most
  commonly
• caused by ischemia due to stroke (Ouch!)
• Aids tumor advance when released by gliomas
  (ouch!)

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Amino Acids

• Inhibitory Amino Acids
• GABA (Gamma aminobutyric acid)
• Direct or indirect action (depending on type of
  receptor
• Main inhibitory neurotransmitter in the brain
• - Selectively permeable to Cl- (hyperpolarizes
  memb.)
• Cerebral cortex, cerebellum, interneurons
  throughout brain and spinal cord
• Inhibitory effects augmented by alcohol and
  benzodiazepines (antianxiety drugs like Valium
  and Librium) and barbiturates
• - these drugs increase the number of GABA
  receptors and thus enhance the inhibitory
  activity of GABA
• Decreased GABA inhibition amy lead to epilepsy

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Neurotransmitters Peptides

• Neuropeptide receptors are all G-protein linked
• Alter levels of intracellular second messengers
• Include
• Substance P mediator of pain signals
• Neuropeptide Y - stimulates appetite and food
  intake
• Beta endorphin, dynorphin, and enkephalins
• Opiods include
• Endorphins, Enkephalins, Dynorphin
• Act as natural opiates, reducing our perception
  of pain
• Found in higher concentrations in marathoners and
  women who have just delivered
• Bind to the same receptors as opiates and
  morphine

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Neurotransmitters Novel Messengers

• Nitric oxide (NO)
• Same substance produced by sublingual
  nitroglycerin produces to increase vasodilation
  in relief of angina
• A short-lived toxic gas diffuses through
  post-synaptic membrane to bind with intracellular
  receptor (guanynyl cyclase)
• Is a free radical and therefore highly reactive
  compound
• Do not confuse with laughing gas (nitrous
  oxide)
• Is involved in learning and memory
• Important in control of blood flow through
  cerebro-vasculature
• Some types of male impotence treated by
  stimulating NO release (Viagra)
• Viagra ? NO release ? smooth muscle relaxation ?
  increased blood flow ? erection
• Cant be taken when other pills to dilate
  coronary b.v. taken

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Functional Classification of Neurotransmitters

• Two classifications excitatory and inhibitory
• Excitatory neurotransmitters cause
  depolarizations (e.g., glutamate)
• Inhibitory neurotransmitters cause
  hyperpolarizations (e.g., GABA)

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Functional Classification of Neurotransmitters

• Some neurotransmitters have both excitatory and
  inhibitory effects
• Determined by the receptor type of the
  postsynaptic neuron
• Example acetylcholine
• Excitatory at neuromuscular junctions with
  skeletal muscle (nicotinic receptor)
• Inhibitory in cardiac muscle (muscarinic receptor)